WO2016152955A1 - Dérivé d'amine cyclique et son utilisation à des fins médicales - Google Patents

Dérivé d'amine cyclique et son utilisation à des fins médicales Download PDF

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WO2016152955A1
WO2016152955A1 PCT/JP2016/059298 JP2016059298W WO2016152955A1 WO 2016152955 A1 WO2016152955 A1 WO 2016152955A1 JP 2016059298 W JP2016059298 W JP 2016059298W WO 2016152955 A1 WO2016152955 A1 WO 2016152955A1
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imidazol
oxopropyl
cyclic amine
mmol
reaction
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PCT/JP2016/059298
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English (en)
Japanese (ja)
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秀二 宇田川
康弘 盛田
直樹 泉本
克彦 伊関
俊介 岩野
智也 三好
祐二 長田
徹郎 是枝
正徳 村上
元明 白木
圭 ▲高▼橋
系裕 大信田
恵理子 東
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東レ株式会社
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Priority to US15/560,581 priority Critical patent/US10117853B2/en
Priority to CA2980259A priority patent/CA2980259C/fr
Priority to ES16768858T priority patent/ES2770924T3/es
Priority to EP16768858.9A priority patent/EP3275879B1/fr
Priority to JP2016520700A priority patent/JP6642422B2/ja
Priority to BR112017020118-6A priority patent/BR112017020118B1/pt
Priority to MX2017011129A priority patent/MX2017011129A/es
Priority to CN201680006326.2A priority patent/CN107207462B/zh
Publication of WO2016152955A1 publication Critical patent/WO2016152955A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a cyclic amine derivative and its pharmaceutical use.
  • Pain is an experience with an unpleasant sensation or an unpleasant emotion that occurs when tissue damage is or is likely to occur. Pain is mainly classified as nociceptive pain, neuropathic pain or psychogenic pain, depending on the cause. In addition, fibromyalgia is known as a pain of unknown cause.
  • Neuropathic pain is pathological pain caused by abnormal functioning of the peripheral or central nervous system itself, and is caused by direct damage or compression of nerve tissue even though nociceptors are not subjected to noxious stimulation. This refers to the pain that occurs.
  • Anticonvulsants, antidepressants, anxiolytics, or antiepileptic drugs are used as therapeutic agents for neuropathic pain.
  • Fibromyalgia is a disease with systemic pain as the main symptom and psychological and autonomic nervous system symptoms as secondary symptoms.
  • As the therapeutic agent for fibromyalgia pregabalin approved in the United States and Japan and duloxetine and milnacipran approved in the United States are mainly used.
  • Non-steroidal anti-inflammatory drugs, opioid compounds, antidepressants, anticonvulsants and antiepileptic drugs that are not approved for the treatment of fibromyalgia are also used.
  • the therapeutic effects of nonsteroidal anti-inflammatory drugs and opioid compounds are generally considered to be low (Non-patent Document 1).
  • Patent Document 1 discloses that certain types of substituted piperidines have cardiotonic activity.
  • Patent Document 2 discloses that an imidazole derivative exhibits an FXa inhibitory action.
  • Patent Document 3 discloses the possibility that substituted piperidines have a medicinal effect on overweight or obesity.
  • Patent Document 4 discloses that imidazole derivatives exhibit analgesic action.
  • the substituted piperidines described in Patent Document 1 are suggested to be effective for migraine, and the imidazole derivatives described in Patent Document 4 are disclosed to have analgesic action.
  • the imidazole derivative described in Patent Document 2 and the substituted piperidines described in Patent Document 3 have no description or suggestion regarding analgesic action.
  • an object of the present invention is to provide a compound showing a strong analgesic action against pain, particularly neuropathic pain and / or fibromyalgia.
  • a cyclic amine derivative having a strong analgesic action against pain, particularly neuropathic pain and / or fibromyalgia.
  • the present invention provides a cyclic amine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
  • A represents a group represented by the formula (IIa) or (IIb);
  • the stereochemistry of the asymmetric carbon marked with * is S configuration, R 1 represents an alkyl group having 3 to 8 carbon atoms, and when A represents a group represented by the formula (IIa), n is 2
  • A represents a group represented by the formula (IIb), n represents 1.
  • a in the above cyclic amine derivative is preferably a group represented by the formula (IIa).
  • the above cyclic amine derivatives are (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) propanoic acid n -Butyl, (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) propanoic acid n-hexyl, ( S) -3- (2- (3- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) propanoic acid n-heptyl and (S) -3 -(2- (3- (3- (dimethyl
  • a in the above cyclic amine derivative is preferably a group represented by the formula (IIb).
  • the above cyclic amine derivatives include 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) acetate n-propyl, 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) n-butyl acetate, 2- (2- (3- (4-morpholinopiperidin-1-yl) ) -3-Oxopropyl) -1H-imidazol-1-yl) n-pentyl acetate, 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazole- 1-yl) acetic acid n-hexyl, 2- (2- (3- (4-morpholinopiperidin
  • the present invention also provides a medicament containing the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the drug is preferably an analgesic, and more preferably a neuropathic pain therapeutic agent or a fibromyalgia therapeutic agent.
  • the present invention also provides a pharmaceutical composition containing the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, a pharmacologically acceptable excipient, and the like. .
  • the present invention also provides a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for use as a medicament.
  • the present invention also provides a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for use in the treatment of pain.
  • the pain is preferably neuropathic pain or fibromyalgia.
  • the present invention also provides use of the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for treating pain.
  • the pain is preferably neuropathic pain or fibromyalgia.
  • the present invention also provides use of the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof in the manufacture of a medicament for treating pain.
  • the pain is preferably neuropathic pain or fibromyalgia.
  • the present invention also relates to a method for treating pain, wherein a therapeutically effective amount of a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof is administered to a patient in need of treatment.
  • a method comprising:
  • the pain is preferably neuropathic pain or fibromyalgia.
  • cyclic amine derivative of the present invention or a pharmacologically acceptable salt thereof exhibits a strong analgesic action against pain, particularly neuropathic pain and fibromyalgia
  • analgesics particularly neuropathic pain therapeutic agents And / or can be used as a therapeutic agent for fibromyalgia.
  • the cyclic amine derivative of the present invention is characterized by being represented by the following general formula (I).
  • A represents a group represented by the formula (IIa) or (IIb);
  • the stereochemistry of the asymmetric carbon marked with * is S configuration, R 1 represents an alkyl group having 3 to 8 carbon atoms, and when A represents a group represented by the formula (IIa), n is 2
  • A represents a group represented by the formula (IIb), n represents 1.
  • a in the above cyclic amine derivative is preferably a group represented by the formula (IIa).
  • the above cyclic amine derivatives are (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) propanoic acid n -Butyl, (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) propanoic acid n-hexyl, ( S) -3- (2- (3- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) propanoic acid n-heptyl and (S) -3 -(2- (3- (3- (dimethyl
  • a in the above cyclic amine derivative is preferably a group represented by the formula (IIb).
  • the above cyclic amine derivatives include 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) acetate n-propyl, 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) n-butyl acetate, 2- (2- (3- (4-morpholinopiperidin-1-yl) ) -3-Oxopropyl) -1H-imidazol-1-yl) n-pentyl acetate, 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazole- 1-yl) acetic acid n-hexyl, 2- (2- (3- (4-morpholinopiperidin
  • C3-C8 alkyl group means a C3-C8 linear, branched or cyclic saturated hydrocarbon group, for example, n-propyl group, isopropyl group, cyclopropyl group N-butyl group, sec-butyl group, isobutyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, n-pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-heptyl group, cycloheptyl Group, n-octyl group or cyclooctyl group.
  • cyclic amine derivative (I) Specific examples of preferred compounds of the cyclic amine derivative represented by the above general formula (I) (hereinafter, cyclic amine derivative (I)) are shown in Table 1-1 and Table 1-2, but the present invention is not limited thereto. It is not something.
  • cyclic amine derivative (I) contains isomers, such as an enantiomer and a stereoisomer, any one isomer and mixtures thereof are also included in cyclic amine derivative (I).
  • isomers due to conformation may be generated, and such isomers and mixtures thereof are also included in the cyclic amine derivative (I).
  • the target isomer can be obtained by a known method or a method analogous thereto. For example, when the enantiomer exists in the cyclic amine derivative (I), the enantiomer separated from the cyclic amine derivative (I) is also included in the cyclic amine derivative (I).
  • the target enantiomer is obtained by a known means (for example, using an optically active synthetic intermediate, or a known method for a racemic mixture of the final product or a method analogous thereto (for example, optical resolution)). Obtainable.
  • the cyclic amine derivative (I) may be labeled with an isotope.
  • Examples of the labeled isotope include 2 H, 3 H, 13 C, 14 C, 15 N, 15 O, 18 O and / or Or 125 I is mentioned.
  • Examples of the pharmacologically acceptable salt of the cyclic amine derivative (I) include inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide; or oxalate, malonate, Citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, salicylate, xinafoate, pamo And organic acid salts such as acid salts, ascorbates, adipates, methanesulfonates, p-toluenesulfonates and cinnamates. In addition, these salts may form hydrates, solvates or crystalline polymorphs.
  • the cyclic amine derivative (I) can be synthesized according to the production method described below.
  • the cyclic amine derivative (I) obtained by the following production method can be isolated and purified by a known means (for example, solvent extraction, recrystallization and / or chromatography), and can be purified by a known method or a method analogous thereto. Can be converted into a salt.
  • the cyclic amine derivative (I) is obtained in the form of a salt, it can be converted to the cyclic amine derivative (I) or other desired salt by a known method or a method analogous thereto.
  • a protecting group may be introduced into these groups, and the protecting group is deprotected as necessary after the reaction. By doing so, the target compound can be obtained.
  • hydroxyl-protecting group examples include a trityl group, an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group), or a substituted silyl group (eg, trimethylsilyl group, triethylsilyl group, or tert-butyldimethylsilyl group). .
  • amino-protecting group examples include an alkylcarbonyl group having 2 to 6 carbon atoms (for example, acetyl group), a benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (for example, tert-butoxycarbonyl group or benzyloxy group) Carbonyl group), an aralkyl group having 7 to 10 carbon atoms (for example, benzyl group) or a phthaloyl group.
  • alkylcarbonyl group having 2 to 6 carbon atoms for example, acetyl group
  • benzoyl group an alkyloxycarbonyl group having 2 to 8 carbon atoms (for example, tert-butoxycarbonyl group or benzyloxy group) Carbonyl group)
  • an aralkyl group having 7 to 10 carbon atoms for example, benzyl group
  • a phthaloyl group examples include an alkylcarbonyl group having 2 to 6 carbon atoms (for example
  • Examples of the protecting group for the carboxyl group include an alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group, or a tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group).
  • the deprotection of the protecting group varies depending on the type of the protecting group, but is in accordance with a known method (for example, Greene, TW, “Green's Protective Groups in Organic Synthesis”, Wiley-Interscience) or a method equivalent thereto. It can be carried out.
  • the cyclic amine derivative (I) can be obtained, for example, by subjecting the compound (III) and the compound (IV) to a condensation reaction using a condensing agent in the presence or absence of a base.
  • Examples of the base used in the condensation reaction include aromatic amines such as pyridine and lutidine; or triethylamine, triisopropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, and N-methyl.
  • aromatic amines such as pyridine and lutidine
  • tertiary amines such as piperidine, N-methylpyrrolidine, N-methylmorpholine or diisopropylethylamine (DIEA).
  • the amount of base used in the condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of compound (III).
  • Examples of the condensing agent used in the condensation reaction include O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), cyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (EEDQ), carbonyldiimidazole (CDI), diethyl Phosphorylcyanide, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-Methylmorpholinium Rorido (DMTMM), isobut
  • condensing agents can be used alone or in combination with N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBT). ) Or an additive such as 4-dimethylaminopyridine (DMAP).
  • HONSu N-hydroxysuccinimide
  • HOBT hydroxybenzotriazole
  • HOOBT 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine
  • DMAP 4-dimethylaminopyridine
  • the amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of compound (III).
  • the amount of compound (IV) used in the condensation reaction is preferably 0.5 to 5 mol, more preferably 0.8 to 2 mol, relative to 1 mol of compound (III).
  • the condensation reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include aromatic amines such as pyridine; halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; ethers such as tetrahydrofuran or 1,4-dioxane; N, N— Amides such as dimethylformamide or N-methylpyrrolidone; alcohols such as methanol, ethanol or 2-propanol; or aliphatic nitriles such as acetonitrile or propionitrile. These mixed solvents may be used.
  • an aromatic amine such as pyridine
  • the condensation reaction can be performed in the absence of a base.
  • the reaction temperature in the condensation reaction is preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 to 100 ° C.
  • the reaction time in the condensation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 60 hours.
  • Chlorination step of cyclic amine derivative (I) The pharmacologically acceptable salt of the cyclic amine derivative (I) can be obtained, for example, by a chlorination reaction by mixing the cyclic amine derivative (I) and an acid.
  • Examples of the acid used for the chlorination reaction include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid Organic acids such as trifluoroacetic acid, maleic acid, gluconic acid, benzoic acid, salicylic acid, xinafoic acid, pamoic acid, ascorbic acid, adipic acid, methanesulfonic acid, p-toluenesulfonic acid or cinnamic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid
  • Organic acids such as trifluoroacetic acid, male
  • the chlorination reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include aliphatic alcohols such as methanol, ethanol or isopropanol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or ethylene glycol dimethyl ether; N, N-dimethylformamide or N-methyl.
  • Amides such as pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Aliphatic nitriles such as acetonitrile or propionitrile; Ketones such as acetone or 2-butanone; Esters such as ethyl acetate, methyl acetate or n-butyl acetate; Or water is mentioned. These mixed solvents may be used.
  • R 2 represents an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group. Each other symbol has the same definition as above. ]
  • Compound (VII) can be obtained by subjecting compound (V) and compound (VI) to a condensation reaction using a condensing agent in the presence or absence of a base.
  • compound (V) and a salt thereof can be used.
  • the salt in this case include the same salts as the above pharmacologically acceptable salts.
  • Examples of the base used in the condensation reaction include aromatic amines such as pyridine and lutidine; or triethylamine, triisopropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, and N-methyl.
  • aromatic amines such as pyridine and lutidine
  • tertiary amines such as piperidine, N-methylpyrrolidine, N-methylmorpholine or diisopropylethylamine (DIEA).
  • the amount of base used in the condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of compound (V).
  • Examples of the condensing agent used in the condensation reaction include O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), cyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (EEDQ), carbonyldiimidazole (CDI), diethyl Phosphorylcyanide, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-Methylmorpholinium Rorido (DMTMM), isobut
  • condensing agents can be used alone or in combination with N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBT). ) Or an additive such as 4-dimethylaminopyridine (DMAP).
  • HONSu N-hydroxysuccinimide
  • HOBT hydroxybenzotriazole
  • HOOBT 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine
  • DMAP 4-dimethylaminopyridine
  • the amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of compound (V).
  • the amount of compound (VI) used in the condensation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 1.5 mol, relative to 1 mol of compound (V).
  • the condensation reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include aromatic amines such as pyridine; halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; ethers such as tetrahydrofuran or 1,4-dioxane; N, N— Amides such as dimethylformamide or N-methylpyrrolidone; alcohols such as methanol, ethanol or 2-propanol; or aliphatic nitriles such as acetonitrile or propionitrile. These mixed solvents may be used.
  • an aromatic amine such as pyridine
  • the condensation reaction can be performed in the absence of a base.
  • the reaction temperature in the condensation reaction is preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 to 100 ° C.
  • the reaction time in the condensation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 60 hours.
  • Examples of the base used for the hydrolysis reaction include lithium hydroxide, potassium hydroxide, and sodium hydroxide.
  • the amount of base used in the hydrolysis reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, relative to 1 mol of compound (VII).
  • the hydrolysis reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • examples of such a solvent include aliphatic alcohols such as methanol, ethanol, and propanol; or water. These mixed solvents may be used.
  • the reaction temperature in the hydrolysis reaction is preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 to 100 ° C.
  • the reaction time in the hydrolysis reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.
  • L represents a leaving group, for example, a chlorine atom, a bromine atom, or an iodine atom is mentioned.
  • R 3 represents an aralkyl group having 7 to 10 carbon atoms, and examples thereof include a benzyl group. Each other symbol has the same definition as above.
  • Compound (IX) can be obtained by olefination reaction using Compound (VIII) and an olefination reagent in the presence or absence of a base.
  • Examples of the base used for the olefination reaction include sodium hydride.
  • the amount of base used in the olefination reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of compound (VIII).
  • olefination reagent used in the olefination reaction examples include Horner-Emmons reagent such as benzyl dimethylphosphonoacetate; or Wittig reagent such as benzyl 2- (triphenylphosphoranylidene) acetate.
  • Horner-Emmons reagent or Wittig reagent a commercially available product can be used as it is.
  • the amount of the olefination reagent used in the olefination reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, relative to 1 mol of compound (VIII).
  • the olefination reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • examples of such a solvent include aromatic hydrocarbons such as toluene, chlorobenzene and xylene; ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N, N-dimethylformamide and N-methylpyrrolidone; Or aliphatic nitriles, such as acetonitrile or propionitrile, are mentioned. These mixed solvents may be used.
  • the reaction temperature in the olefination reaction is preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 to 100 ° C.
  • the reaction time in the olefination reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.
  • Compound (X) can be obtained by an alkylation reaction in which an alkylating reagent (LI) is allowed to act after deprotonation of compound (IX) with a base.
  • an alkylating reagent (LI) is allowed to act after deprotonation of compound (IX) with a base.
  • Examples of the base used in the alkylation reaction include metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; or n-butyllithium, sec-butyllithium Alternatively, butyllithiums such as tert-butyllithium can be used.
  • the amount of base used in the alkylation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, relative to 1 mol of compound (IX).
  • the amount of the alkylating reagent (LI) used in the alkylation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, relative to 1 mol of compound (IX).
  • the alkylation reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • examples of such a solvent include ethers such as tetrahydrofuran or 1,4-dioxane; amides such as N, N-dimethylformamide or N-methylpyrrolidone; or aliphatic nitriles such as acetonitrile or propionitrile. Can be mentioned. These mixed solvents may be used.
  • the reaction temperature in the alkylation reaction is preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 to 100 ° C.
  • the reaction time in the alkylation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.
  • Step 6 Compound (XI) is obtained by an alkylation reaction in which an alkylating reagent (LI) is allowed to act after deprotonation of compound (VIII) with a base.
  • Examples of the base used in the alkylation reaction include metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; or n-butyllithium, sec-butyllithium Alternatively, butyllithiums such as tert-butyllithium can be used.
  • the amount of base used in the alkylation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, relative to 1 mol of compound (VIII).
  • a commercially available compound can be used as the alkylating reagent (LI) used in the alkylation reaction.
  • the amount of the alkylating reagent (LI) used in the alkylation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of compound (VIII).
  • the alkylation reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • examples of such a solvent include aliphatic hydrocarbons such as heptane and hexane; and ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane. These mixed solvents may be used.
  • the reaction temperature in the alkylation reaction is preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 to 100 ° C.
  • the reaction time in the alkylation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.
  • Step 7 Compound (X) can be obtained by olefination reaction using compound (XI) and an olefination reagent in the presence or absence of a base.
  • Examples of the base used for the olefination reaction include sodium hydride.
  • the amount of the base used in the olefination reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, relative to 1 mol of compound (XI).
  • olefination reagent used in the olefination reaction examples include Horner-Emmons reagent such as benzyl dimethylphosphonoacetate; or Wittig reagent such as benzyl 2- (triphenylphosphoranylidene) acetate.
  • Horner-Emmons reagent or Wittig reagent a commercially available product can be used as it is.
  • the amount of the olefination reagent used in the olefination reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, relative to 1 mol of compound (XI).
  • the olefination reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • examples of such a solvent include aromatic hydrocarbons such as toluene, chlorobenzene and xylene; ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N, N-dimethylformamide and N-methylpyrrolidone; Or aliphatic nitriles, such as acetonitrile or propionitrile, are mentioned. These mixed solvents may be used.
  • the reaction temperature in the olefination reaction is preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 to 100 ° C.
  • the reaction time in the olefination reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.
  • transition metal catalyst used in the reduction reaction examples include palladium-carbon.
  • the amount of the transition metal catalyst used in the reduction reaction is preferably from 0.1 to 100% by weight, more preferably from 1 to 50% by weight, based on the compound (X).
  • the reduction reaction is generally performed in a solvent.
  • a solvent that does not inhibit the reaction is appropriately selected.
  • examples of such a solvent include aliphatic hydrocarbons such as heptane or hexane; or aliphatic alcohols such as methanol, ethanol or propanol. These mixed solvents may be used.
  • the reaction temperature in the reduction reaction is preferably 0 to 80 ° C, more preferably 10 to 40 ° C.
  • the reaction time in the reduction reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.
  • Step 9 Compound (XIV) is obtained by a reductive amination reaction between compound (XII) and compound (XIII).
  • the reductive amination reaction can be performed according to a known method (for example, Journal of Organic Chemistry, 2003, Vol. 68, p. 770-779) or a method analogous thereto.
  • the deprotection of the protecting group varies depending on the type of the protecting group, but is in accordance with a known method (for example, Greene, TW, “Green's Protective Groups in Organic Synthesis”, Wiley-Interscience) or a method equivalent thereto. It can be carried out.
  • the analgesic action of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, particularly the therapeutic effect of neuropathic pain and fibromyalgia can be evaluated using an appropriate animal model.
  • Suitable animal models for neuropathic pain include, for example, the mouse or rat sciatic partial ligation model (Malberg et al., Pain, 1998, Vol. 76, p. 215-222) or mouse or rat spinal nerve ligation. Model (Kim et al., Pain, 1992, 50, 355-363).
  • Suitable animal models for fibromyalgia include, for example, the rat fibromyalgia model (Sluka et al., Journal of Pharmacology and Experimental Therapeutics, 2002, 302, p. 1146-1150; Nagakura et al., Pain, 2009, 146, p. 26-33; Sluka et al., Pain, 2009, 146, p. 3-4).
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof has an excellent analgesic action, particularly a therapeutic effect for neuropathic pain and / or fibromyalgia, and therefore is used as a medicine. And is preferably used as an analgesic, and particularly preferably used as a therapeutic agent for neuropathic pain and / or a therapeutic agent for fibromyalgia.
  • cyclic amine derivative (I) or a pharmacologically acceptable salt thereof can be expected to reduce central side effects, long-term administration in the treatment of neuropathic pain and / or fibromyalgia. Is possible.
  • neuropathic pain examples include cancer pain, herpes zoster pain, postherpetic neuralgia, AIDS-related neuralgia, diabetic neuropathic pain, or trigeminal neuralgia.
  • Fibromyalgia refers to symptoms diagnosed by a specialist as fibromyalgia. Diagnosis by a specialist is generally performed with reference to classification criteria of the American College of Rheumatology.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is also useful for treating acute and chronic pain.
  • Acute pain is usually short-term, but includes post-operative pain, post-extraction pain, or trigeminal neuralgia.
  • Chronic pain is usually defined as pain lasting for 3-6 months and includes somatic and psychogenic pain, including rheumatoid arthritis, osteoarthritis or postherpetic neuralgia .
  • the pharmaceutical containing the cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof as an active ingredient is a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey or human).
  • a mammal eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey or human.
  • it when administered to humans, it exhibits excellent analgesic action, particularly therapeutic effects on neuropathic pain and / or fibromyalgia.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is used as a medicine
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is incorporated as it is or with a pharmaceutically acceptable carrier.
  • it can be administered orally or parenterally.
  • Examples of dosage forms for oral administration of a pharmaceutical containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient include tablets (including sugar-coated tablets and film-coated tablets), pills, Examples include granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions, and suspensions.
  • Examples of dosage forms for parenteral administration of a pharmaceutical containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient include, for example, injections, infusions, infusions, and suppositories. And a coating agent or a patch.
  • a suitable base for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester
  • a suitable base for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester
  • the preparation of the above dosage form can be performed according to a known production method generally used in the pharmaceutical field. In this case, if necessary, it is produced by containing excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers and the like generally used in the pharmaceutical field. be able to.
  • Tablets can be prepared, for example, by containing an excipient, a binder, a disintegrant, or a lubricant. Pills and granules can be prepared, for example, by containing an excipient, a binder or a disintegrant. Moreover, powders and capsules can be prepared, for example, by containing an excipient.
  • the syrup preparation can be prepared, for example, by adding a sweetener.
  • the emulsion or suspension can be prepared, for example, by containing a surfactant, suspending agent or emulsifier.
  • excipient examples include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate or calcium sulfate.
  • binder examples include starch paste, gum arabic solution, gelatin solution, tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
  • disintegrant examples include starch and calcium carbonate.
  • Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • sweetener examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin and simple syrup.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agent examples include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite.
  • emulsifier examples include gum arabic, tragacanth, gelatin, and polysorbate 80.
  • a pharmaceutical containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient is prepared in the above-mentioned dosage form, a colorant generally used in the pharmaceutical field, storage Agents, fragrances, flavoring agents, stabilizers, thickeners and the like can be added.
  • the daily dose of a pharmaceutical containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient varies depending on the patient's condition or body weight, the type of compound, the administration route, and the like.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is used in an amount of 1 to 1000 mg as an active ingredient in 1 to 3 times. It is preferable to administer them separately.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as the active ingredient amount is 0.01 per kg body weight.
  • Administration by intravenous injection in the range of ⁇ 100 mg is preferred.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is particularly preferably orally administered because of its excellent oral absorbability.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic or preventive effect, or to reduce the dose.
  • Other drugs in this case include, for example, antidepressants such as amitriptyline, milnacipran or duloxetine; anxiolytics such as alprazolam; anticonvulsants such as carbamazepine; local anesthetics such as lidocaine; and sympathetic nerves such as adrenaline.
  • Agonists such as ketamine
  • GABA transaminase inhibitors such as sodium valproate
  • calcium channel blockers such as pregabalin
  • serotonin receptor antagonists such as risperidone
  • GABA receptor function promoters such as diazepam
  • Anti-inflammatory drugs such as diclofenac.
  • the solvent name shown in the NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (manufactured by JEOL Ltd.).
  • the chemical shift is represented by ⁇ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruplex line), quint, respectively.
  • ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology). All solvents were commercially available. For flash column chromatography, YFLC W-prep2XY (manufactured by Yamazen) was used.
  • the raw material and intermediate of the cyclic amine derivative (I) were synthesized by the method described in the following reference examples.
  • the commercially available compound was used about the compound which is used for the synthesis
  • the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in hydrochloric acid (1.0N) and extracted with ethyl acetate.
  • the aqueous layer was made basic by adding a 48% aqueous sodium hydroxide solution, and extracted with dichloromethane.
  • the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in methanol (25.0 mL), concentrated hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 40 ° C. for 12 hr.
  • the reaction solution was concentrated to dryness and then dissolved in distilled water.
  • the precipitated white solid was collected by filtration, washed with diethyl ether (8.0 mL), dried at room temperature for 36 hours, and then 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) acetic acid n-hexyl hydrochloride (0.0809 g, 0.159 mmol, 73%) (hereinafter, the compound of Example 16) was obtained as a white solid.
  • the precipitated white solid was collected by filtration, washed with diethyl ether (8.0 mL), dried at room temperature for 36 hours, and then 2- (2- (3- (4-morpholinopiperidin-1-yl) -3-oxopropyl) -1H-imidazol-1-yl) acetic acid n-octyl hydrochloride (0.755 g, 0.141 mmol, 66%) (hereinafter, the compound of Example 20) was obtained as a white solid.
  • Example 21 Effect on mouse sciatic nerve partial ligation model: Using a mouse partial sciatic nerve ligation model (Seltzer model) that can evaluate neuropathic pain, the analgesic action of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof was examined.
  • Skzer model mouse partial sciatic nerve ligation model
  • a mouse partial sciatic nerve ligation model was prepared according to the method of Seltzer et al. (Malberg et al., Pain, 1998, Vol. 76, p. 215-222).
  • CD1 ICR mouse (5-week-old, male; Charles River, Japan) was anesthetized with sodium pentobarbital (70 mg / kg, intraperitoneal administration) to expose the sciatic nerve in the right hind leg thigh
  • a group in which the sciatic nerve was triple-ligated with a half circumference using an 8-0 silk thread (Natsume Seisakusho) under a microscope was defined as a sciatic nerve partial ligation group, and the group that had not been ligated only by exposing the sciatic nerve was sham operated Grouped.
  • neuropathic pain (hereinafter von Frey test) was performed by acclimatizing a mouse for at least 1 hour in a measurement acrylic cage (Natsume Seisakusho) installed on a net, and then applying a filament (0.16 g pressure) Using North Coast Medical or neuroscience), mechanical tactile stimulation that presses the filament to the sole of the right hind limb for 3 seconds is repeated 3 times at intervals of 3 seconds, and the strength of escape behavior when mechanical tactile stimulation is applied is scored (0: no response, 1: slow and slight escape behavior with respect to the stimulus, 2: quick escape behavior with respect to the stimulus without flinching (behavior shaking the foot quickly) or licking (foot licking behavior), 3 : Quick escape action with flinching or licking), and the total of the three scores (hereinafter, It was the score) as an indicator of pain.
  • mice of the sciatic nerve partial ligation group were treated with the compound of Example 4, 6, 8, 10, 12, 14, 16, 18 or 20 (the compounds of Examples 4, 6 and 8 were 1 to 10 mg / kg, the compounds of Examples 16 and 18 are 0.1 to 10 mg / kg, respectively.
  • the compounds of Examples 10, 12 and 14 are 0.01 to 10 mg / kg and the compounds of Example 20, respectively.
  • pregabalin (10 mg / kg; KEMPROTEC) as a positive control was orally administered dissolved in distilled water.
  • a group in which the compound of Example 4, 6, 8, 10, 12, 14, 16, 18, or 20 was administered to a mouse of the sciatic nerve partial ligation group was referred to as “sciatic nerve partial ligation + compound of Example 4” group, "Sciatic nerve partial ligation + compound of Example 6” group, “Sciatic nerve partial ligation + compound of Example 8” group, “Sciatic nerve partial ligation + compound of Example 10” group, “Sciatic nerve partial ligation + Example” 12 compounds “group,” sciatic nerve partial ligation + compound of Example 14 "group,” sciatic nerve partial ligation + compound of Example 16 “group,” sciatic nerve partial ligation + compound of Example 18 “group,” sciatic bone " The “partial nerve ligation + compound of Example 20” group was used, and the group administered with pregabalin was the “sciatic nerve partial ligation + pregabalin” group.
  • the group in which distilled water was orally administered to mice in the sciatic nerve partial ligation group was referred to as the “sciatic nerve partial ligation + distilled water” group
  • the group in which distilled water was orally administered to mice in the sham operation group was referred to as “sham surgery + Distilled water "group.
  • the von Frey test was conducted before oral administration of the test compound (pre value), 1 hour, 2 hours and 3 hours after oral administration.
  • FIGS. The results are shown in FIGS.
  • the horizontal axis shows the time (hr) after administration of the test compound.
  • the evaluation of drug efficacy was performed by using the “Sciatic nerve partial ligation + distilled water” group (“sciatic nerve partial ligation + distilled water” in the figure) at each measurement time as a control, and two unmatched Welch tests or Shirley-Williams tests Statistical processing was performed.
  • the ⁇ or # mark in the figure is statistically significant in comparison with the “sciatic nerve partial ligation + distilled water” group ( ⁇ : Welch test (p ⁇ 0.05), #: Shirley-Williams test. (P ⁇ 0.025)).
  • Example 4 the compound of Example 4, 6, 8, 10, 12, 14, 16, 18 or 20 was orally administered ("sciatic nerve partial ligation in the figure + Examples 4, 6, 8").
  • 10, 12, 14, 16, 18 or 20 compound shows a statistically significant analgesic action, similar to the positive control pregabalin (" sciatic nerve partial ligation + pregabalin "in the figure). It was.
  • Example 22 Effect on rat fibromyalgia model: Using a rat fibromyalgia model capable of evaluating fibromyalgia, the analgesic action of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof was examined.
  • Fibromyalgia model rats generally used in basic research of fibromyalgia (Sluka et al., Journal of Pharmaceutical and Experimental Therapeutics, 2002, Vol. 302, p. 1146-1150; Nagakura et al., Pain, 2009, Vol.146, p.26-33; Sluka et al., Pain, 2009, vol.146, p.3-4) 100 ⁇ L of acidic physiological saline adjusted to pH 4.0 was used to produce isoflurane continuous inhalation anesthesia.
  • Allodynia in each rat was measured on the 7th day from the first administration of acidic physiological saline, and fibromyalgia was observed in rats with a 50% response threshold (average value of right hind limb and left hind limb) of 2 g to 6 g.
  • the rats were selected as onset fibromyalgia model rats and used in the following administration experiments.
  • Allodynia was measured using a von Frey filament (North Coast Medical) according to the method described in publicly known literature (Chaplan et al., Journal of Neuroscience Methods, 1994, Vol. 53, p.55-63). .
  • the fibromyalgia model rats thus obtained were divided into groups so that the 50% response threshold (average value of right hind limb and left hind limb) was equal between groups, and 7 days from the first administration of acidic physiological saline. Eyes were administered test compounds to fibromyalgia model rats.
  • the compound of Example 6 or 18 (the compound of Example 6 is 10 to 100 mg / kg, the compound of Example 18 is 1 to 100 mg / kg) is dissolved in distilled water and orally administered to fibromyalgia model rats.
  • acid physiological saline + compound of Example 6 in FIG. 10, "Acid physiological saline + compound of Example 18" in FIG. 11).
  • pregabalin (10 mg / kg; KEMPROTEC) was dissolved in distilled water and orally administered
  • acidic physiological saline + pregabalin in FIG. 10 or 11
  • distilled water was orally administered to a fibromyalgia model rat
  • acidic physiological saline + distilled water in FIG.
  • distilled water was orally administered to rats that did not develop fibromyalgia ("physiological saline + distilled water" in FIG. 10 or 11).
  • the analgesic effect was evaluated by measuring the allodynia of each rat 1 hour and 3 hours after oral administration. At that time, the 50% reaction threshold value in the allodynia measurement before the oral administration of the test compound on the seventh day from the first administration day of the acidic physiological saline was defined as the pre value.
  • FIG. 10 or 11 shows the results of oral administration of the compound of Example 6 or 18, respectively.
  • the horizontal axis of the figure shows the pre-oral administration (pre value) of the compound of Example 6 or 18 and the elapsed time (hr) from the oral administration.
  • the ⁇ or # mark in the figure indicates the uncorresponding t-test or Welch test with the “acidic saline solution + distilled water” group (“acidic saline solution + distilled water” in the figure) for each measurement time as a control.
  • Williams test or Shirley-Williams test is statistically significant ( ⁇ : t test or Welch test (p ⁇ 0.05), #: Williams test or Shirley-Williams test (p ⁇ 0. 025)).
  • the group to which the compound of Example 6 or 18 was orally administered (“acidic physiological saline + the compound of Example 6 or 18” in the figure) was the group to which pregabalin as a positive control was orally administered (“acidic physiological solution in the figure”).
  • saline solution + pregabalin As in the case of “saline solution + pregabalin”), allodynia observed in the fibromyalgia model rats was statistically significantly improved as compared with the “acidic saline solution + distilled water” group.
  • the cyclic amine derivative of the present invention or a pharmacologically acceptable salt thereof can exert an analgesic action on pain, particularly neuropathic pain or fibromyalgia, it can be used as a medicament for pain symptoms.

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Abstract

La présente invention concerne un composé ayant un effet analgésique puissant sur la douleur, en particulier sur la douleur neuropathique et/ou sur la fibromyalgie. La présente invention concerne un dérivé d'amine cyclique représenté par formule chimique (1), ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2016/059298 2015-03-24 2016-03-24 Dérivé d'amine cyclique et son utilisation à des fins médicales WO2016152955A1 (fr)

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US15/560,581 US10117853B2 (en) 2015-03-24 2016-03-24 Cyclic amine derivative and pharmaceutical use thereof
CA2980259A CA2980259C (fr) 2015-03-24 2016-03-24 Derive d'amine cyclique et son utilisation a des fins medicales
ES16768858T ES2770924T3 (es) 2015-03-24 2016-03-24 Derivado de amina cíclica y utilización farmacéutica del mismo
EP16768858.9A EP3275879B1 (fr) 2015-03-24 2016-03-24 Dérivé d'amine cyclique et son utilisation pharmaceutique
JP2016520700A JP6642422B2 (ja) 2015-03-24 2016-03-24 環状アミン誘導体及びその医薬用途
BR112017020118-6A BR112017020118B1 (pt) 2015-03-24 2016-03-24 Derivado aminado cíclico, medicamento e agente analgésico bem como uso do derivado aminado cíclico
MX2017011129A MX2017011129A (es) 2015-03-24 2016-03-24 Derivado de amina ciclica y uso farmaceutico del mismo.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005507906A (ja) * 2001-10-12 2005-03-24 ノボ　ノルディスク　アクティーゼルスカブ 置換ピペリジン類、およびヒスタミンｈ３受容体関連疾患の治療のためのその使用
JP2005527519A (ja) * 2002-03-14 2005-09-15 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 新規な置換ピペリジン、これら化合物を含む医薬組成物、その使用及びその調製方法
WO2006137465A1 (fr) * 2005-06-24 2006-12-28 Shionogi & Co., Ltd. Dérivé hétérocyclique azoté
WO2013147160A1 (fr) * 2012-03-29 2013-10-03 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
WO2015046403A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2163150B (en) 1984-07-19 1988-05-25 Sandoz Ltd 3-aminopropoxyaryl derivatives
JP2006008664A (ja) 2004-05-21 2006-01-12 Takeda Chem Ind Ltd イミダゾール誘導体、その製造法及び用途
CA2977614C (fr) * 2015-02-27 2023-01-17 Toray Industries, Inc. Derive d'amine cyclique et utilisation pharmaceutique de celui-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005507906A (ja) * 2001-10-12 2005-03-24 ノボ　ノルディスク　アクティーゼルスカブ 置換ピペリジン類、およびヒスタミンｈ３受容体関連疾患の治療のためのその使用
JP2005527519A (ja) * 2002-03-14 2005-09-15 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 新規な置換ピペリジン、これら化合物を含む医薬組成物、その使用及びその調製方法
WO2006137465A1 (fr) * 2005-06-24 2006-12-28 Shionogi & Co., Ltd. Dérivé hétérocyclique azoté
WO2013147160A1 (fr) * 2012-03-29 2013-10-03 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
WO2015046403A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3275879A4 *

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JPWO2016152955A1 (ja) 2018-01-11
CN107207462A (zh) 2017-09-26
EP3275879A4 (fr) 2018-09-19
CA2980259A1 (fr) 2016-09-29
BR112017020118A2 (pt) 2018-05-29
ES2770924T3 (es) 2020-07-03
EP3275879B1 (fr) 2020-01-15
US20180104221A1 (en) 2018-04-19
MX2017011129A (es) 2017-11-28
EP3275879A1 (fr) 2018-01-31
CA2980259C (fr) 2024-02-06
JP6642422B2 (ja) 2020-02-05
CN107207462B (zh) 2020-03-06

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